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Beta-Blockers (β-Adrenoceptor Antagonists) - Complete Pharmacology Summary
Source: Katzung's Basic and Clinical Pharmacology, 16th Edition
1. Mechanism of Action
Beta-blockers competitively and reversibly block β-adrenoceptors, preventing activation by catecholamines (norepinephrine, epinephrine). The key physiological effects depend on which receptor subtype is blocked:
| Receptor | Location | Effect of Blockade |
|---|---|---|
| β1 | Heart, JGA of kidney | ↓ HR, ↓ contractility, ↓ AV conduction, ↓ renin release |
| β2 | Bronchi, vascular smooth muscle, liver, uterus | Bronchoconstriction, vasoconstriction, ↓ glycogenolysis |
| β3 | Adipose tissue | ↓ Lipolysis |
2. Classification (Key Properties to Know)
A. Selectivity (β1 vs. non-selective)
| Drug | β1-Selective (Cardioselective)? |
|---|---|
| Atenolol, Metoprolol, Bisoprolol, Betaxolol, Esmolol, Acebutolol, Nebivolol | YES (β1-selective) |
| Propranolol, Nadolol, Timolol, Pindolol, Sotalol, Carteolol | NO (non-selective) |
| Carvedilol, Labetalol | NO + also block α1 receptors |
Exam tip: Remember cardioselective drugs with the mnemonic "AMEBBN" - Acebutolol, Metoprolol, Esmolol, Bisoprolol, Betaxolol, Nebivolol (+ Atenolol). Cardioselectivity is LOST at high doses.
B. Intrinsic Sympathomimetic Activity (ISA / Partial Agonism)
Some β-blockers are partial agonists - they weakly stimulate the receptor while blocking full agonists. They cause less resting bradycardia.
- ISA (+): Acebutolol, Pindolol, Carteolol, Labetalol, Celiprolol
- ISA (-): Propranolol, Atenolol, Metoprolol, Bisoprolol, Esmolol, Nadolol, Timolol, Carvedilol
C. Additional α1 Blockade (Combined α/β Blockers)
- Labetalol - oral, t½ ~5 hours, 30% bioavailability (also has ISA)
- Carvedilol - oral, t½ 7-10 hours, 25-35% bioavailability (no ISA)
- Both cause vasodilation → useful in heart failure and hypertension with less reflex tachycardia
D. Lipid Solubility (Determines CNS Penetration)
| Lipid Solubility | Drugs | Clinical Note |
|---|---|---|
| High | Propranolol, Carvedilol, Metoprolol (moderate) | Cross BBB → more CNS side effects (nightmares, depression) |
| Low | Atenolol, Bisoprolol, Nadolol, Sotalol | Less CNS penetration |
E. Membrane-Stabilizing (Local Anesthetic) Effect
Propranolol, Acebutolol, Labetalol, Metoprolol have sodium channel-blocking properties. Only clinically relevant in overdose (causes wide QRS).
3. Key Individual Drugs - Quick Reference Table
| Drug | Selectivity | ISA | Half-life | Special Features |
|---|---|---|---|---|
| Propranolol | Non-selective | No | 3-6 h | High first-pass effect; most lipid-soluble; most toxic in OD |
| Atenolol | β1 | No | 6-9 h | Low lipid solubility; renally excreted; once daily |
| Metoprolol | β1 | No | 3-4 h (XL ~20h) | Moderate lipid; IV for MI/arrhythmias |
| Bisoprolol | β1 | No | 9-12 h | High bioavailability (80%); HF mortality reduction |
| Esmolol | β1 | No | 10 minutes | IV only; used for acute rate control (AF, surgery) |
| Carvedilol | Non-selective + α1 | No | 7-10 h | Heart failure mortality reduction |
| Labetalol | Non-selective + α1 | Yes | 5 h | HTN in pregnancy; hypertensive emergencies |
| Nebivolol | β1 | No | 10-12 h | Releases NO → vasodilation (unique mechanism) |
| Sotalol | Non-selective | No | 12 h | Class III antiarrhythmic effect (K⁺ channel block); prolongs QT |
| Timolol | Non-selective | No | 4 h | Ophthalmic use for glaucoma |
| Pindolol | Non-selective | Yes | 3-4 h | Highest ISA; may cause tachycardia in overdose |
4. Pharmacokinetics
- Absorption: Most are well absorbed orally; peak in 1-3 hours
- First-pass effect: Propranolol has very high first-pass metabolism → large oral-IV dose difference and high inter-individual variability
- Drugs with high bioavailability (>80%): Betaxolol (~90%), Pindolol (~90%), Penbutolol, Sotalol (~90%), Carteolol (85%), Bisoprolol (80%)
- Esmolol is IV only (t½ 10 min) - hydrolyzed by red blood cell esterases
5. Clinical Uses
| Indication | Drug of Choice / Notes |
|---|---|
| Hypertension | Any β-blocker; labetalol preferred in pregnancy |
| Angina pectoris | Reduces O₂ demand (↓ HR, contractility, wall tension) |
| Acute MI / Post-MI | Metoprolol, atenolol (IV then oral) - reduce infarct size & mortality |
| Heart Failure (stable, systolic) | Metoprolol succinate, bisoprolol, carvedilol - only 3 proven to reduce mortality |
| Arrhythmias | Rate control in AF; sinus tachycardia; SVT; sotalol for ventricular arrhythmias |
| Thyroid storm | Propranolol (non-selective - also blocks peripheral T4→T3 conversion) |
| Pheochromocytoma | ONLY after adequate α-blockade first (to prevent unopposed α vasoconstriction) |
| Glaucoma | Timolol, betaxolol (eye drops - ↓ aqueous humor production) |
| Migraine prophylaxis | Propranolol, timolol, metoprolol |
| Essential tremor | Propranolol |
| Anxiety / situational fear | Propranolol (blocks peripheral sympathetic symptoms) |
| Portal hypertension / varices | Propranolol, nadolol (non-selective needed - splanchnic vasoconstriction via β2) |
6. Adverse Effects
| Side Effect | Mechanism | Notes |
|---|---|---|
| Bradycardia, heart block | β1 blockade | CI in sick sinus syndrome, 2nd/3rd degree AV block |
| Bronchoconstriction | β2 blockade | Dangerous in asthma/COPD - use cardioselective drugs with caution |
| Masking of hypoglycemia | β2 blockade | Blocks tachycardia warning; sweating still occurs (cholinergic) |
| Fatigue, cold extremities | ↓ cardiac output, β2 vasoconstriction | Common |
| CNS effects | Lipid-soluble drugs cross BBB | Nightmares, depression, insomnia |
| Sexual dysfunction | Reduced cardiac output | More common with older agents |
| Dyslipidemia | β2 blockade | ↑ TG, ↓ HDL |
| Hyperkalemia | β2 blockade on K⁺ uptake |
7. Contraindications
- Absolute: Severe bradycardia, high-degree AV block, cardiogenic shock, uncontrolled asthma, pheochromocytoma without prior α-blockade
- Relative: Chronic obstructive pulmonary disease (use cardioselective), peripheral artery disease, diabetes (may mask hypoglycemia), depression (lipid-soluble agents)
8. Abrupt Withdrawal - "Rebound Effect"
Abrupt discontinuation can precipitate angina, MI, or rebound hypertension, especially in patients with ischemic heart disease. This is due to upregulation of β-receptors during chronic blockade. Always taper slowly.
9. Drug Interactions
- Verapamil / Diltiazem + β-blocker = severe bradycardia and AV block (dangerous combination)
- Insulin / Oral hypoglycemics = masking of hypoglycemia
- NSAIDs = may blunt antihypertensive effect
- Antiarrhythmics (amiodarone) = additive bradycardia
10. Overdose Management
- Most toxic: Propranolol (Na⁺ channel block + CNS penetration; 2-3x therapeutic dose can cause serious toxicity)
- Features: Bradycardia, hypotension, cardiac conduction block (wide QRS), seizures
- Drugs with ISA (pindolol) in OD: may cause tachycardia and hypertension instead
- Treatment: IV fluids, atropine, β-agonists are generally ineffective
- Glucagon (5-10 mg IV) is the key antidote - raises cAMP via a β-receptor-independent mechanism
High-Yield Exam Mnemonics
- "A MAN BB" for β1-selective: Acebutolol, Metoprolol, Atenolol, Nebivolol, Bisoprolol, Betaxolol (+ Esmolol)
- ISA drugs: "PICAL" - Pindolol, (Celiprolol), Acebutolol, Carteolol, Labetalol
- HF mortality reducers: Metoprolol succinate (XL), Bisoprolol, Carvedilol (only these 3)
- Nebivolol is unique: it is the only β-blocker that also stimulates NO release
- Propranolol is the prototype for everything non-selective needs
- Esmolol: ultra-short (10 min), IV only, used perioperatively
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